The major aims of this project have been accomplished through establishment of a large community based family study of adult probands who participate in comprehensive clinical and biologic assessments followed by comparable evaluations of their adult and child relatives. Recruitment of probands and evaluation of relatives are now near completion and analyses of the findings are underway. To date, we have enrolled 815 probands, 1288 relatives, and 175 children into the study from community, clinical, and other recruitment sources. Approximately 500 probands and about 1000 of their relatives have completed the study, of which 500 have been evaluated at the NIH Clinical Center. Probands represent a large range of disorders including mood, anxiety, sleep, migraine, and cardiovascular in addition to controls. We are now completing interviews with relatives who had not previously participated in the study, particularly children who do not live in the local geographic area. We have also begun to follow up families in order to track changes in their health over time. In order to identify the core features of mood and anxiety disorders and their overlap with sleep problems, cardiovascular diseases and migraine, we have established a set of clinical, psychophysiological and neuropsychological measures. The comprehensive set of measures in the study are divided into three components: (1) clinical information that includes a semi-structured diagnostic interview for mood and anxiety disorders, structured diagnostic interviews for major headache syndromes and for sleep disorders, family history of psychiatric disorders, sleep disorders and headache syndromes, and a series of self-reported measures of symptoms, sleep patterns and personality, medical history, family structure, history and function, and major life and family events; (2) in person evaluation at the NIH Clinical Center that includes physical and neurological examination; autonomic nervous system evaluation using tilt and valsalva maneuver; laboratory measures of metabolic, cardiovascular, and immunologic function; psychophysiologic evaluation including startle reflex and eyeblink reflex; structural magnetic resonance imaging; a computerized cognitive assessment battery; and olfactory function; and (3) two-week assessment of daily activities including an electronic diary that assesses daily rhythms including mood, anxiety, sleep, stress, activity, diet, and social activities; heart rate reactivity using a holter monitor; activity and sleep using an actiwatch; and saliva hormones collected four times per day. In the past year, we have been running preliminary analyses on several of these clinical components and working with external collaborators to design and implement analyses of all of the measures in the study. This study has yielded substantial methodological developments including the development and validation of a structured diagnostic interview for headache syndromes (Lateef et al, 2012); systematic assessment of the validity of the NIMH Family Study Diagnostic Interview for Affective Spectrum Disorders that was developed for this study compared to the Structure Clinical Interview for DSM-IV (SCID); and the validity of the NIMH Sleep Diagnostic Interview also developed for this study compared with sleep disorder diagnoses made by sleep experts (Merikangas et al, in press). We have completed the primary analyses of the familial aggregation of mood disorder subtypes, their patterns of comorbidity, and their co-aggregation in relatives, and have submitted the principal paper that reports these findings. Likewise, we have also completed analyses of the familial aggregation of migraine and comorbid conditions. The major findings confirm the familial aggregation of bipolar disorder and major depression that has been found in earlier family studies of mood disorders but in a community based sample that suspended diagnostic hierarchies of earlier diagnostic systems. The most important finding that emerged from this study is the independent familial transmission of mania and depression suggesting that these two mood states may represent distinct underlying diatheses. The lack of familial aggregation of hypomania suggests that the bipolar spectrum concept may not be a valid entity. We also found strong evidence for familial specificity of atypical depression in probands and interviewed relatives, thereby confirming the validity of this subtype of depression. Additional analyses that are now being investigated include the familial aggregation of subtypes of sleep disorders, early manifestations of mood and anxiety disorders in offspring of parents with mood spectrum disorders, and heritability analyses of both disorders and underlying traits. During the past several months, we have begun to examine the non-clinical measures as well, with substantial progress in analysis of the eyeblink reflex, actigraphy, olfactory measures and neuropsychologic function. We have also conducted extensive analyses of links between cardiovascular disease and risk factors, migraine and depression in other data sets to develop specific hypotheses for the analyses of the family study data. Some intriguing findings that have emerged include: greater reactivity of the eyeblink reflex among those with migraine with aura compared to those without aura and non-headache controls; demonstrated bi-directional links between mood states and activity, with greater associations among those with bipolar disorder; greater variability in activity patterns among those with major depression; and increased orienting to cues in those with migraine with aura, and decreased speed of attention among those with depression. Public Health Impact: Integration of the clinical, neuropsychological and psychophysiological measures within families will allow us an in-depth analysis of the biological mechanisms crucial for mood and anxiety disorders and their underlying diatheses. This will not only lead to a better understanding of these conditions, and assist in identifying common genetic mechanisms, but may also lead to the development of novel treatment options and possible strategies for prevention and early intervention in those with elevated risk for these conditions. Future Plans: During the next year, we plan to follow up the probands and relatives to update the diagnostic status, and repeat the measures of circadian rhythms of activity, sleep and cognitive and mood states to test their stability and seasonal changes. We will complete enrollment of children under age 18 and follow up 150 youth who have already participated in the study. The majority of effort will be devoted to continuing analyses of the data in three areas: familial aggregation, heritability and co-aggregation of subtypes of depression, sleep disorders and patterns, migraine subtypes and cardiovascular disease; (2) activity and daily regulation of emotional states, sleep, stress, and hormonal indices of stress; and (3) association between mood disorders subtypes with the full range of biologic measures including autonomic reactivity, cardiovascular, immunologic and metabolic laboratory measures, psychophysiologic function (e.g., startle and eyeblink reflex), neurocognitive function, olfaction and neuroimaging parameters.